Cytarabine, also known as Ara-C or Cytosar, has long been known as a chemotherapeutic agent in the treatment of acute myelogenous leukemia. Cytarabine has the formula:

The active ingredients of the pharmaceutical composition of the present invention comprise cytarabine derivatives of the formula I:
wherein R1, R2 and R3 are independently selected from hydrogen and C18- and C20-saturated and monounsaturated acyl groups, with the proviso that R1, R2 and R3 cannot all be hydrogen.
Cytarabine has limited efficiency against solid tumors (Frei et al., Cancer Res. 29 (1969), 1325-1332; Davis et al., Oncology, 29 (1974), 190-200; Cullinan et al., Cancer Treat. Rep. 61 (1977), 1725-1726), and even in the treatment of leukemia cytarabine has found only limited use due to its very short biological half-life and its high toxicity.
With a view to overcome these difficulties, a number of workers have prepared and tested pro-drug derivatives of cytarabine. For example, Hamamura et al. investigated 3′-acyl and 3′,5′-diacyl derivatives of cytarabine (J. Med. Chem. 19 (1976) No. 5, 667-674). These workers prepared and tested numerous cytarabine derivatives with saturated or unsaturated ester groups containing from 2 to 22 carbon atoms, and they found that many of the compounds showed a higher activity against L1210 Leukemia in mice than the parent nucleoside alone.
Although work has continued on ester pro-drugs based on cytarabine, including 3′- and 5′-acyl derivatives (see, for instance, Rubas et al. in Int. J. Cancer, 37, 1986, pages 149-154 who tested liposomal formulations of 5′-oleyl-cytarabine against L1210 Leukemia and Melanoma B16) to date no such drugs have become available to the clinician.
A main reason why cytarabine is not used in the treatment of solid tumors is the rapid clearance of the active drug from cancer cells and plasma. It is apparently not possible to achieve significant intracellular levels of drug in the neoplastic tissue, even though the tumor in question is sensitive to cytarabine in vitro. We have earlier shown that the derivatives of formula I have prolonged half life and altered tissue distribution which are of great importance for the therapeutic effect of these products (WO 97/05154).
The development of resistant cancer cells is a severe problem in the current chemotherapy of cancer. It was found earlier that one of derivatives of formula I, elacytarabine (5′-O-(trans-9″-octadecenoyl)-1-β-D-arabinofuranosylcytosine), shows the same effect against Cis-platin resistant cells (NHIK 3025/DDP) and MDR resistant cells (A549) as against the corresponding non-resistant cell lines. This is because the ester derivatives are not substrates for the cellular drug-efflux mechanisms, such as the “gp 120 MDR pump”, responsible for the phenomenon seen as multi drug resistance.
Nevertheless, formulation of a therapeutically effective amount of the poorly soluble derivatives of formula (I) into a pharmaceutical composition suitable for parenteral administration represents a problem. For the sake of intravenous administration of the said derivatives, the composition of the excipients should be selected so that the said derivatives are solubilised. The cytarabine derivatives of formula (I) are amphiphilic and have poor solubility both in water and in oils. This limits the choice of potential excipients that can solubilise them. As an example, elacytarabine has a solubility of <0.1 μg/ml in deionised water and <1 μg/ml in phosphate buffer pH 7.4 at 25° C. Also, earlier formulation studies showed that elacytarabine did not dissolve appropriately in soybean oil based emulsions, which confirms the low solubility of the drug in oils.
If the formulation is a particulate system, there are certain requirements for the size of the particles in the formulations for intravenous administration. Moreover, parenteral products must be sterile and often sterile filtration is the only viable method for pharmaceutical particulate systems. This means that the particle size of these formulations must be smaller than 220 nm (0.22 μm), which is the pore size of the sterile filters. In practice and for an industrial scale process, the particles should be much smaller to avoid filter clogging.
Another issue is that the daily recommended dose for intravenous elacytarabine when given as a single therapy is recently established at 2000 mg/m2. This means that for an average patient with a surface area of 1.8 m2, the total daily dose of elacytarabine will be 3600 mg. This introduces even further challenges: a) requirement of increasing the concentration of the drug in the formulation in order to limit the parenteral administration of unacceptably large volumes of liquids to the patients, b) avoiding the use of antioxidants and preservatives, which although added at small amounts, will add up to an unacceptable level of the total administered amount, and c) limiting the quantities of the added surfactants and co-solubilizers due to the same reason as above.
Finally, the ester derivatives of formula (I) are prone to hydrolytic degradation in physiological pH, the rate of which depends on the type of the derivative and the buffer. This represents further challenges both to the formulation and to the manufacturing process parameters. It is normally preferred that a pharmaceutical product be ready-to-use. If ready-to-use, then the said derivatives should be protected from hydrolytic degradation in the aqueous environment of the parenteral formulation during its entire shelf-life period.
The present invention presents a solution to all the above problems.